An Activity-Based Fluorescent Probe for Imaging Fluctuations of Peroxynitrite (ONOO-) in the Alzheimer's Disease Brain

Peroxynitrite (ONOO^-) plays a critical role in Alzheimer's disease (AD), and the association between ONOO^- and AD is inexplicit. To reveal the ONOO^- influxes in AD brains, an activatable activity-based fluorescence probe Rd-DPA3 was rationally designed by a structure-modulated strategy. Taking advantage of ONOO^--sparked two-step cascade reactions of a novel chemical trigger, Rd-DPA3 specifically responds to ONOO^- among 0.3 mM other ROS and varied proteins, accompanied by an intensive fluorescence enhancement (F/F₀ = 50). Moreover, with the mitochondria-targeting ability, Rd-DPA3 can efficiently monitor the alternations of intracellular ONOO^- levels in the cerebral cells during oxidative stress. Significantly, due to NIR emission and superb blood-brain barrier (BBB) crossing ability, Rd-DPA3 is capable of in vivo imaging cerebral ONOO^- influxes and illustrating an age-dependent accumulation of native ONOO^- in AD mice brains. This work discloses that Rd-DPA3 would be beneficial for AD diagnosis, treatment evaluation, and potential pathogenesis study.

https://doi.org/10.1002/anie.202206894